DESCRIPTION (Verbatim from the Applicant): After the molecular cloning of the PTH/PTHrP receptor (PTH1R) and its gene, we identified activating mutations in Jansen's metaphyseal chondrodysplasia (JMC), a genetic disorder characterized by short-limbed dwarfism and severe PTH-/PTHrP-independent hypercalcemia. Since the PTH1R is abundantly expressed in kidney, bone and growth plates, expression of mutant PTH1Rs in these tissues provided a plausible explanation for the characteristic laboratory and radiological findings in JMC, and the transgenic expression of mutant PTH1Rs (type II collagen promoter) in mice confirmed that the metaphyseal changes are indeed caused by constitutively active receptors. Surprisingly, trabecular bone volume appears to be increased in JMC patients, while cortical bone is unchanged or diminished; equivalent findings were made in transgenic mice expressing the mutant PTH1R under the control of the type I collagen promoter. Taken together these findings indicate that endosteal and periosteal bone formation are differently regulated. To further explore the PTH1Rs role in bone formation, we now propose to pursue the following Specific Aims. In Aim 1, we propose to develop a mouse model of Jansen's disease by replacing the wild-type PTH1R gene with a mutant gene containing an activating mutation (i.e. the H223R/M226L mutation, or other mutations with higher constitutive activity). This animal will allow us to explore, in more detail than is possible in patients, the impact of activated PTH1Rs on mineral ion homeostasis, bone metabolism, and growth plate development. In Aim 2, we will determine whether inverse agonists can reduce the constitutive activity of the mutant PTH1R in kidney and bone. Besides providing further confirmation that persistent receptor activation is indeed responsible for all JMC-specific changes, the "Jansen" mouse will thus provide a model to explore details of the PTH1R's role in bone metabolism, and to determine its biological role(s) in other tissues. In Aim 3, we plan to search for additional PTH1R mutations in JMC patients and to assess in these and previously characterized individuals the changes in trabecular and cortical bone formation.